Figures
- FIGURE 1
Schematic representation of the downstream signalling pathways of neurofibromin. Neurofibromin inhibits the activity of Ras by its guanosine triphosphatase activity. Loss of activity of neurofibromin in neurofibromatosis type 1 (NF1) leads to the activation of different pathways mediated by RAS, namely the mitogen-activated protein kinase cascade leading to activation of ERK and mammalian target of rapamycin (mTOR) pathway. These pathways activate nuclear transcription factors and are responsible for endothelial cell differentiation, proliferation, increased survival and migration. PI3K: phosphatidylinositol 3-kinase; Rheb: Ras homolog enriched in brain; TSC: tuberous sclerosis protein.
- FIGURE 2
Mechanisms leading to development of pulmonary hypertension (PH) in neurofibromatosis type 1 (NF1). Green indicates pre-capillary hypertension and red indicates post-capillary hypertension.
Tables
- TABLE 1
Classification of group 5 pulmonary hypertension according to European Society for Cardiology/European Respiratory Society guidelines
5. Pulmonary hypertension with unclear and/or multifactorial mechanisms 5.1 Haematologic disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis, neurofibromatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension Reproduced from [1] with permission.
- TABLE 2
Diagnostic criteria for neurofibromatosis type 1 (NF1) [9]
Two or more of the criteria below are required for diagnosis: Six or more café au lait macules (>0.5 cm in children or >1.5 cm in adults) Two or more cutaneous or subcutaneous neurofibromas or one plexiform neurofibroma Axillary or groin freckling Optic pathway glioma Two or more Lisch nodules (iris hamartomas seen on slit lamp examination) Bony dysplasia (sphenoid wing dysplasia, bowing of long bone±pseudoarthrosis) First-degree relative with NF1 - TABLE 3
Published articles on pulmonary hypertension associated with neurofibromatosis type 1
First author [ref.] Sex Age years CT scan NYHA PO2 mmHg FVC % FEV1 % DLCO % mPpa mmHg CI L·min·m−2 PVR Wood units Treatment Course Porterfield [21] Female 56 Interstitial markings in lower lobes. bullae in apex (radio) III 33 7 35 Calcium antagonist Samuels [22] Male 51 Bilateral perfusion defects III 57 77 71 49 3.4 3.0 Endarterectomy Improvement after surgery Aoki [23] Female 16 Normal II 67 116 84 79 49 2.1 15.1 Calcium antagonist and anticoagulants Aggravation and then treatment with i.v. prostanoids. Death 2 years after the diagnosis Female 70 Normal III 48 38 2.3 12.0 Anticoagulant and isosorbide dinitrate Aggravation and then treatment with i.v. protanoids García Hernandez [24] Male 44 Normal III 30 107 110 62 i.v. prostanoids Improvement and then death some years after diagnosis Engel [25] Female 60 Lung cysts and T-7 schwannoma III 85 90 48 50 2.3 10 ERA, PDE5 inhibitor and i.v. prostanoids Clinical improvement Female 69 Normal III 105 119 66 60 2.3 11 PDE5 inhibitor Clinical improvement Stewart [26] Female 72 Mosaic perfusion IV 66 73 35 2.7 5.4 Calcium antagonists and i.v. prostanoids Death from respiratory failure Female 56 Mild ground-glass attenuation in the upper lobes and lung cysts III 83 76 41 68 1.6 i.v. prostanoids Death 2 years after diagnosis from respiratory failure Male 68 Lung cysts 49 2.4 5.4 Calcium antagonists Death 6 years after diagnosis from RH failure Female 33 Mosaic perfusion 34 38 53 1.3 24.4 ERA and PDE5 inhibitor Death 1 year after starting treatment Simeoni [27] Female 51 Nodular lesions and schwannoma in the upper mediastinum III 72 65 ERA Stable after 2 years of treatment Montani [28] Female 59 Normal III 73 104 59 48 2.0 12.0 Anticoagulants, ERA and i.v. prostanoids Death after 6 months Female 63 Moderate pulmonary fibrosis with large bullae III 58 52 45 27 52 1.9 14.4 Anticoagulants, PDE5 inhibitor, ERA and i.v. prostanoids Death after 42 months Female 53 Lung cysts and interstitial infiltrate III 109 25 47 2.7 8.0 Anticoagulants, PDE5 inhibitor, ERA and i.v. prostanoids Death after 46 months Female 69 Normal III 67 103 39 54 2.3 14.4 PDE5 inhibitor and ERA, prostanoids declined Alive at 36 months but more severe Male 66 Mosaic perfusion and mild emphysema III 69 (3 L) 104 48 43 2.1 9.3 Anticoagulants, PDE5 inhibitor and ERA Alive at 8 months Female 63 Lung cysts III 51 69 69 23 36 3.3 Anticoagulants and ERA Alive at 18 months. On a waiting list for lung transplant Female 53 Lung cysts III 79 (4 L) 83 29 NA 31 4.7 No Alive at 3 months Female 61 Lung cysts and interstitial infiltrate III 40 95 24 37 2.3 7.1 Anticoagulants, ERA, i.v. prostanoids then lung transplantation Alive 8 months after diagnosis and 1 month after lung transplantation Gumbiene [29] Female 30 Mosaic perfusion IV 115 111 55 49 2.5 15 Anticoagulants, PDE5 inhibitor and ERA Death after 3 months Malviya [30] Male 34 Mosaic perfusion II 58 2.7 19 PDE5 inhibitor and balloon atrial septostomy Alive 8 months after diagnosis Male 44 Mosaic perfusion and localised fibrotic lesion IV 74 66 44 48 1.7 26.5 ERA and PDE5 inhibitor Alive after 15 months and improved Tamura [31] Female 30 NA II 39 i.v. prostanoid then PDE5 inhibitor and ERA then sorafenib Alive 6 years after the diagnosis Martignac [32] Female 64 Lung cysts, ground-glass opacities and suspect mass III 64 72 26 62 1.9 21.4 Anticoagulants, ERA and PDE5 inhibitor Death after 4 months Kamdar [33] Female 69 NA 39 23 PDE5 inhibitor and i.v. prostanoid Improvement and alive after 12 months Giannakoulas [34] Female 57 Normal 84 1.9 27.1 Anticoagulants, ARE and PDE5 inhibitor then balloon atrial septostomy followed by i.v. prostanoids Improvement and alive after 24 months Chaddha [35] Female 63 Lung cysts, ground-glass opacities and interlobular septal thickening IV 60 2.1 14 PDE5 inhibitor and i.v. prostanoids (stopped after pulmonary oedema) Pulmonary oedema under vasodilator. Death after 3 months Küçük [36] Female 46 Mosaic perfusion pattern II 91 100 93 85 2.9 16 Calcium antagonists and ERA Improvement Poble [37] Female 55 Lung cysts III 68 93 104 49 41 2 19 Anticoagulants, PDE5 inhibitor and ERA Improvement and alive after 9 months Palot [38] Female 55 Intrathoracic meningocele and scoliosis IV 53 51 68 30 4.9 Noninvasive ventilation Improvement after 1 month CT: computed tomography; NYHA: New York Heart Association; PO2: oxygen tension; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLCO: diffusing capacity of the lung for carbon monoxide; mPpa: mean pulmonary artery pressure; CI: cardiac index; PVR: pulmonary vascular resistance; NA: not available; ERA: endothelin receptor antagonist; PDE5: phosphodiesterase-5.
- TABLE 4
Comparison of key distinguishing features between pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with neurofibromatosis type 1 (PH-NF1)
Idiopathic or heritable PAH PH-NF1 Genetics Main gene mutation BMPR2, ACVRL1, ENG, KCNK3, CAV-1, SMAD9 NF1 Genetic transmission Autosomal dominant Autosomal dominant Epidemiology Estimated prevalence 15 cases per million Prevalence of NF1 is 1 per 3000, prevalence of PH is unknown Sex ratio Female predominance (∼2:1) Female predominance (∼4:1) Clinical examination Dermatological signs Absent Café au lait macules, axillary or groin freckling, subcutaneous neurofibroma Neurological signs Absent Possible optic glioma Right heart catheterisation mPpa, PAWP, PVR Increased mPpa, normal PAWP, increased PVR More severely increased mPpa, normal PAWP, more severely increased PVR Acute vasoreactivity testing ∼10% in idiopathic PAH (predicts long-term CCB response) No case reported Pulmonary function FEV1, FVC, TLC Normal (possible mild reduction) Normal (possible mild reduction) DLCO Normal (possible mild reduction) Severe reduction Imaging Chest HRCT Usually normal parenchyma Ground-glass opacities, lung cysts, lung reticulations V′/Q′ lung scan Usually normal Usually normal Treatment Targeted PAH therapy Improved haemodynamics, functional capacity and clinical outcomes Poor response (based on isolated case reports) BMPR2: bone morphogenetic protein receptor type 2; ACVRL1: activin A receptor type II-like kinase 1; ENG: endoglin; KCNK3: potassium channel subfamily K member 3; CAV-1: caveolin 1; mPpa: mean pulmonary artery pressure; PAWP: pulmonary artery wedge pressure; PVR: pulmonary vascular resistance; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; HRCT: high-resolution computed tomography; V′/Q′: ventilation/perfusion; CCB: calcium channel blocker.
